Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in Western countries, with the lowest five-year relative (1) and 1-year survival rates (2) among commonly diagnosed cancers. PDAC is anticipated to move to the second leading cause of cancer death worldwide by 2020 in the absence of improvements in early detection and/or treatment (3).
Since 1997, Gemcitabine is the only approved first-line treatment for patients with advanced PDAC (2); however, the 5-year survival rate is only 2% (1), with 1-year survival rates ranging from 17 to 23% (2). Recently, phase II and III trials exploring gemcitabine-based combinations with erlotinib (4) or nab-Paclitaxel (5) were found to improve overall survival of patients with a metastatic disease. Thus, the moderate activity of standard gemcitabine and gemcitabine-based regimens strongly encourages new therapeutic research programs such as gene therapy.
The inventors devised in the past decade a highly innovative approach based on therapeutic gene transfer using non-viral vectors to restore SSTR2 expression (encoding for somatostatin receptor subtype 2) that is lost in 95% of PDAC tumors (6). The inventors found that SSTR2-based gene therapy induces a strong bystander antitumoral effect that is antiproliferative, pro-apoptotic, anti-angiogenic, and anti-metastatic (7-12). Resistance to gemcitabine is a major cause of unsatisfactory improvement during pancreatic cancer treatment may help identify novel therapeutic target genes to enhance the efficacy of gemcitabine treatment. DeoxyCytidine Kinase (DCK) phosphorylates gemcitabine to gemcitabine diphosphate in a rate-limiting step. Loss of expression of this key enzyme was recently associated with acquired resistance to gemcitabine in pancreatic cancer cells, in preclinical models (13), and in patients (14). The inventors demonstrated that delivering DCK::UMK fusion gene, encoding for both DCK and Uridylate Monophosphate Kinase (UMK), using non-viral vectors overcomes PDAC-derived cells resistance to gemcitabine (15). Thus, as opposed to many trials for PDAC treatment in which new agents are combined with gemcitabine simply because it is a standard of care, there is a strong rationale to deliver DCK and UMK genes and to treat advanced pancreatic cancer tumors with chemotherapy.
The phase I study was conducted to determine the recommended phase two dose (RPTD) of a clinical-grade, gene therapy product combining for the first time SSTR2, DCK and UMK gene expression, delivered by a non-viral vector, and administered with gemcitabine in patients with advanced pancreatic cancer. The inventors characterized the feasibility, tolerability and toxicity profile of the regimen and examined preliminary efficacy. Pharmacokinetic and biomarker studies were also performed.
Taking into account the risk of these treatments, the increasing number of available therapeutic molecules in pancreatic cancer, the variability of the response to the various treatment, and to optimize the drug prescription, identification of predictive markers of gene therapy and gemcitabine combination may be highly desirable.